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Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.
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Cerebrovascular disease is the second most common cause of cognitive disorders, usually referred to as vascular contributions to cognitive impairment and dementia (VCID) and makes some contribution to about 70 % of all dementias. Despite its importance, research into VCID has lagged as compared to cognitive impairment due to Alzheimer's disease. There is an increasing appreciation that closing this gap requires large national and international collaborations. This paper highlights 24 notable large-scale national and international efforts to advance research into VCID (MarkVCID, DiverseVCID, DISCOVERY, COMPASS-ND, HBC, RHU SHIVA, UK DRI Vascular Theme, STROKOG, Meta VCI Map, ISGC, ENIGMA-Stroke Recovery, CHARGE, SVDs@target, BRIDGET, CADASIL Consortium, CADREA, AusCADASIL, DPUK, DPAU, STRIVE, HARNESS, FINESSE, VICCCS, VCD-CRE Delphi). These collaborations aim to investigate the effects on cognition from cerebrovascular disease or impaired cerebral blood flow, the mechanisms of action, means of prevention and avenues for treatment. Consensus groups have been developed to harmonise global approaches to VCID, standardise terminology and inform management and treatment, and data sharing is becoming the norm. VCID research is increasingly a global collaborative enterprise which bodes well for rapid advances in this field.
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PURPOSE: To evaluate the association between localised vascular and retinal nerve fibre layer (RNFL) loss and genetic risk for glaucoma and cardiovascular disease using polygenic risk scores (PRS). METHODS: 858 eyes were included from 455 individuals with suspect and early manifest primary open angle glaucoma. Eyes were characterised as having localised vascular and/or RNFL wedge-shaped defects by scrutiny of optical coherence tomography angiography (OCTA) and OCT images, respectively. Investigations included associations with pre-established scores for genetic risk of glaucoma and cardiovascular disease in the context of glaucoma risk factors and systemic vascular disease outcomes. RESULTS: Higher genetic risk for glaucoma was associated with both vascular wedge defects and RNFL defects (p < 0.001 and p = 0.020, respectively). A greater genetic risk of glaucoma was associated with the presence of multiple vascular wedges per eye (p = 0.005). Glaucoma progression based on global RNFL loss was associated with vascular and RNFL wedge defects (p ≤ 0.001 and p = 0.008, respectively). The glaucoma PRS was significantly associated with vascular, but not RNFL, wedge defects after controlling for disc haemorrhage (p = 0.007 and p = 0.070, respectively). Vascular wedge defects were not related to the cardiovascular PRS. CONCLUSION: Individuals with a higher genetic risk of glaucoma based on the PRS were more likely to have retinal vascular defects, as well as structural glaucomatous loss, but this did not relate to systemic cardiovascular risk. This possibly implies a local pathophysiology for the vascular defects in some cases, which may have clinical relevance in the early stages of glaucoma and in individuals at high genetic risk.